Preparation of coumarin-3-carboxylic acid



Patented Jan. 4, 1944 7 2,338,569 PREPARATION OF ooUMARm-s- CARBOXYLICACID Luther F. Berhenke, Ezra Monroe, and Edgar C. Britton, Midland,Mich., assignors to The Dow Chemical Company, Midland, Mich., acorporation of Michigan No Drawing. Application May 31, 1941, Serial No.396,190

4 Claims.

This invention concerns the condensation of aromatic aldehydes withmalonic acid and more particularly improvements in the method for thecondensation of salicylaldehyde with malonic acid to formcoumarin-B-carboxylic acid.

The preparation of coumarin-3-carboxylic acid by the condensation ofsalicylaldehyde with malonic acid is well known (cf. Stuart: J. Chem.Soc. 49 366 (1886); and German Patents Nos: 161,171, 164,296, and97,735). According to these teachings, this condensation has heretoforebeen accomplished by heating salicylaldehyde and malonic acid togetherin the presence of amines, amine salts, or acetic acid at temperaturesapproximating 100 C. German Patent 164,296 describes the use ofpiperidine as a catalyst with a resultant yield of 80 per cent ofcoumarin-ZB-carboxylic acid. Stuarts method consists in heating togethera mixture of salicylaldehyde, malonic acid, and glacial acetic acid at100 0., followed by recrystallization of the coumarin-B-carboxylic acid.According to German Patent 161,171 equimolecular proportions ofsalicylaldehyde and malonic acid are heated for several hours on thewater bath with 0.13 molecular proportion of aniline hydrochloride, andaccording to German Patent 97,735 equimolecular proportions of malonicacid and aniline are heated on the water bath with 0.87 molecularproportion of salicylaldehyde.

Disadvantages inherent in these known meth ods are apparent. .The largeamount of either acetic acid or catalyst such as amine or amine saltwhich it is necessary to employ necessitates purification, e. g.,recrystallization, of the coumarin-3-carboxylic acid which involvesconsiderable expense and lowering in yield. Furthermore, in thecondensation to form the coumarin- 3-carboxylic acid two molecularproportions of water are formed. As is known, malonic acid is unstablein the presence of water at temperatures as low as 70 0., beingconverted slowly into acetic acid and carbon dioxide. The rate ofdecomposition increases rapidly with rise in temperature, so that asubstantial portion of the malonic acid is lost through decompositionwhen the reaction is carried out as usual at a temperature ofapproximately 1 C. Knoevenagel (Ber. 31 2618 (1898)) attempted toovercome this difiiculty by allowing equimolecular proportions ofmalonic acid, salicylaldehyde, and aniline to stand in alcoholicsolution at room temperature for 24 hours, but obtained only an 80 percent yield of coumarin-B-carboxylic acid. We have attempted repeatedlyto prepare coumarin-3-carboxylic acid in good yield by the proceduresgiven in the literature using equimolecular proportions ofsalicylaldehyde andmalonic acid at elevated temperatures, but'in no casewas a yield of crude material greater than 91.5 per cent' obtained basedupon the malonic acid used. This yield is, of course, lowered uponcrystallizing to secure a pure product.

It is an object of this invention to provide an improved method for thepreparation of coumarin-B-carboxylic acid, whereby the yield issubstantially improved over that possible with previously known methodsand by means of which a product sufficiently pure for most uses can beobtained directly from the reaction mixture without resorting toadditional purification steps.

We have found that these objects may be attained by dispersingsalicylaldehyde, malonic acid, and small amounts of amines or aminesalts in a liquid water-entraining agent and heating to a temperaturesufiicient to co-distill the entraining agent and the water formedduring the reaction, followed by separation and washing of thecoumarin-S-carboxylic acid product. We have further found that althoughthe reaction may be carried out at widely varying temperatures it occursmost satisfactorily when carried out at temperatures between about 40 C.and about C.

As just indicated, the reaction mixture employed in our process containsas essential ingredients, malonic acid, salicylaldehyde, an amine or anamine salt, e. g., aniline, meta-toluidine, para-aminophenol,salicylidene aniline, aniline hydrochloride, etc., as catalyst, and awater-entraining agent, e. g., hexane, ethylene dichloride, benzene,monochlor-benzene, isopropyl ether, etc. The mixture may also containacetic acid or other lower aliphatic carboxylic acid, e. g., propionicacid, etc., but its presence is not required.

The salicylaldehyde and malonic acid are ordinarily used insubstantially equimolecular proportions, i. e., in the proportions inwhich they react together, but the reaction may be carried out using alarge excess of either reactant, if desired. Anhydrous reactants arepreferred but are not essential since any water introduced into thereaction mixture with the reactants subsequently co-distills with thewater-entraining agent. Although a large number of amines and theirsalts have been found effective as catalysts for the reaction, aromaticamines are usually employed, preferably aniline. It is probable thatwhen amines are used they are converted by the acid in the reactionmixture into the corresponding salt. It may be mentioned that thecontinuous removal of water from the reacting mixture, in accordancewith the invention, favors completion of the reaction and permitsemployment of the catalyst in amount considerably less than the amountsused in prior methods for the production of coumarin-3-carboxylic acid.Less than 10.0 mol per cent of aniline or other amine is used andpreferably less than 5.0 mol per cent,

100 C., and preferably between 50 and 85C.

The relationship between yield and reaction temperature is illustratedin the table given in Example 2. Among the various well-knownwaterentraining agents which may be used to remove water from thereaction mixture are hydrocarbons, halohydrocarbons, ethers, etc.,Water-en training agents which are chemically inert toward the reactantunder the reaction conditions are' preferred. The reaction temperatureis, of course, that at which water and the entraining agent distill fromthe mixture, which temperature is usually somewhat, though not greatly,lower than the boiling point of the entraining agent alone. However,water-entraining agents whose boiling points at atmospheric pressure arelower or higher than the desired reaction temperature may be used, inwhich case the pressure under which the reaction is carried out isincreased or decreased, respectively, to cause the entraining agent toboil at the desired reaction temperature. An amount of the entrainingagent sufficient to maintain the reaction mixture in a semifluidcondition is used advantageously. Entraining agents.

in which coumarin-3-carboxylic acid is relatively insoluble arepreferred since they permit excellent recovery of the product by simplycooling and filtering the reacted mixture. A water-immiscible entrainingagent may advantageously be used, since such agent may be continuouslyseparated from the distillate and returned to the reaction vessel.Alternatively, successive portions of the agent may be added atintervals to replace that distilled or a sufiicient amount may beadded-to the original reaction mixture to carry over substantially allof the water while maintaining the reaction mixture in the desired stateof fluidity.

It has been found advantageous to include a minor proportion of asaturated monobasic aliphatic acid such as acetic or propionic acids inthe reaction mixture since the presence of such acids leads to somewhatsmoother reaction and the isolation of a slightly purer product. Thefunction of the monobasic acid may be to act as a solubilizing agent forthe malonic acid. 0.25'to 1.0 molecular proportion of acetic acid hasbeen used with advantage.

The reaction is complete when water is no longer carried over by theentraining agent. This usually occurs after from 3 to hours of heatingand distilling, but the time depends to a considerable extent, ofcourse, on the boiling point of the water entraining agent and the rateof distillation. When the reaction is complete, the mixture may becooled and filtered to separate the cournarin-3-carboxylic acid, and thelatterwashed with fresh portions of the entraining agent untilsubstantially free from the amine and acetic acid. The washedcoumarin-B-carboxylic acid may be dried, e. g., in a current of warmair, and'after drying is substantially pure. The combined filtrate. andwashings may be saved and used in subsequent reactions for theproduction of coumarin-B-carboxylic acid. Since substantially all of theacetic acid and amine used are found in the filtrate and washings, it isonly necessary to add enough of each to replace that lost during theprocess.

By carrying the reaction out as just described,

coumarin-B-carboxylic acid of good purity may readily be produced innearly quantitative yield.

The following examples describe a number of ways in which the principleof the invention has n been applied, but are not to be construed aslimiting its scope.

EXAMPLE 1 t 122 grams (1 mol) of salicylalclehyde, 104 grams (1 mol) ofmalonic acid, 15.8 grams (0.26 mol) of acetic acid, 2 grams (.02 mol) ofaniline, and 250 cc. of petroleum ether (n-hexane fraction boiling at60'70 C.) were heated together. Co-distillation of water and petroleumether occurred at 60-65 C. The distillate was condensed and thepetroleum ether wa separated from the water and returned continuously tothe reaction flask. As the reaction progressed, thecoumarin-3-carboxylic acid precipitated from the mixture to form a thickslurry. After 8 hours of heating, water was no longer distillingtogether with the petroleum ether. The reaction mixture was then cooledand filtered. The coumarin-3-carboxylic acid was washed on the filterwith fresh petroleum ether, until substantially free from aniline andacetic acid and dried. There was thus obtained grams (1 mol) ofsubstantially pure coumarin-3-carboxylic acid melting at 184-188 C. Thecombined filtrate and washings were saved and used in a subsequentreaction.

EXAMPLE 2 The results of a number of experiments on the preparation ofcoumarin-B-carboxylic acid using water-entraining agents with diiferentboiling.

points are given in the following table. In obtaining this data,reaction mixtures containing equimolecular proportions ofsalicylaldehyde, malonic acid, and acetic acid, together with 0.02molecular proportion of aniline and approximately 200 cc. of theentraining agent noted to each mol of salicylaldehyde were heated tocause smooth distillation until water ceased distilling with theentraining agent. The mixtures were then cooled and filtered and thecoumarin-3- carboxylic acid washed with fresh portions of the entrainingagent and dried. The reaction temperature and time, the boiling point ofthe water-entraining agent used, the per cent yield, and the meltingpoint of the coumarin-3-carboxylic acid isolated are noted for eachexperiment:

TABLE Efiect of boiling point of water-entraining agent on yield ofcoumarin-3-carboxylic acid Other modes of applying the principle of theinvention may be employed instead of those explained, change being madeas regards the process herein disclosed, provided the step or stepsstated by any of the following claims or the equivalent of such statedstep or steps be employed.

We therefore particularly point out and distinctly claim as ourinvention:

1. In a method for preparing coumarin-3-carboxylic acid, the steps whichconsist in heating a mixture comprising substantially equimolecularproportions of salicylaldehyde and malonic acid, not to exceed 0.1molecular proportion of an amine and a water-immiscible water-entrainingagent boiling between about 50 and about 85 C. to co-distill theentraining agent and Water from the reacting mixture and separatingcoumarin-3- carboxylic acid from the reacted mixture.

2. In a method of preparing coumarin-3-carboxylic acid the steps whichconsist in heating a mixture comprising substantially equimolecularproportions of salicylaldehyde and malonic acid, not to exceed 1molecular proportion of acetic acid, not to exceed 0.05 molecularproportion of aniline, and a petroleum fraction boiling between about 60C. and about 70 C. to co-distill the petroleum fraction and water fromthe reacting mixture, separating coumarin-3-carboxylic acid from thereacted mixture, and washing and drying the coumarin-B-carboxylic acid.

3. In a method of preparing coumarin-B-carboxylic acid the steps whichconsist in heating a mixture comprising substantially equimolecularproportions of salicylaldehyde and malonic acid, not to exceed 1molecular proportion of acetic acid, not to exceed 0.05 molecularproportion of aniline, and isopropyl ether to co-distill the isopropylether and Water from the reacting mixture, separatingcoumarin-B-carboxylic acid from the reacted mixture, and washing anddrying the coumarin-3-carboxylic acid.

4. In a method of preparing coumarin-B-carboxylic acid the steps whichconsist in heating a mixture comprising substantially equimolecularproportions of salicylaldehyde and malonic acid,

not to exceed 1 molecular proportion of acetic acid, not to exceed0.05mo1ecular proportion of aniline, and benzene to co-distill thebenzene and water from the reacting mixture, separatingcoumarin-3-carboxylic acid from the reacted mixture, and washing anddrying the coumarin- 3-carboxylic acid.

LUTHER. F. BERHENKE.

EZRA MONROE.

EDGAR C. BRITTON.

